Published online before print March 29, 2004, doi: 10.1161/01.CIR.0000125700.33637.B1
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2004;109:1966-1972.)
© 2004 American Heart Association, Inc.
Clinical Investigation and Reports |
Increased Expression of Interleukin-1 in Coronary Artery Disease With Downregulatory Effects of HMG-CoA Reductase Inhibitors
From the Research Institute of Internal Medicine (T.W., A.Y., C.S., S.S.F., P.A., J.K.D.), Department of Cardiology (T.W., C.S., J.K.D.), Center of Occupational and Environmental Medicine (T.H., S.H.T.), Section of Clinical Immunology and Infectious Diseases (S.S.F., P.A.), Lipid Clinic (A.G.S.), Rikshospitalet, University of Oslo, Oslo; and the Department of Cardiology, Bærum Hospital (L.G.), Bærum, Norway.
Correspondence to Torgun Wæhre, MD, Research Institute of Internal Medicine, Rikshospitalet, N-0027 Oslo, Norway. E-mail torgun.wahre{at}klinmed.uio.no or torgunw@broadpark.no
Received July 8, 2003; de novo received December 10, 2003; revision received February 3, 2004; accepted February 5, 2004, 2003.
Background— Inflammation is important in atherogenesis. Interleukin (IL)-1 is the prototypic inflammatory cytokine. We hypothesized a dysbalance between inflammatory and anti-inflammatory mediators in the IL-1 family in coronary artery disease (CAD) and a possible modulation of these mediators by HMG-CoA inhibitors (statins).
Methods and Results— In a microarray screening experiment examining peripheral blood mononuclear cells (PBMCs) from 6 CAD patients and 4 healthy control subjects, IL-1ß was identified as 1 of 25 genes whose expression were upregulated in CAD and downregulated by statins. In the following, we studied the role of IL-1ß and related mediators in CAD. Our major findings were as follows. (1) Although mRNA levels of IL-1
and IL-1ß were markedly reduced in PBMCs from CAD patients after 6 months of simvastatin (20 mg/d, n=15) and atorvastatin (80 mg/d, n=15) therapy, the reduction in IL-1 receptor antagonist (IL-1Ra) was more modest. Statins also reduced the spontaneous release of IL-1ß and IL-1Ra from PBMCs in CAD patients. (2) mRNA levels of IL-1, IL-1ß, and IL-1Ra were increased in PBMCs from patients with stable (n=20) and unstable (n=20) angina compared with healthy control subjects (n=15). Although the unstable patients had particularly high levels of IL-1ß and IL-1, IL-1Ra was not correspondingly increased. (3) IL-1ß induced release of proatherogenic cytokines from PBMCs, whereas atorvastatin partly abolished this effect.
Conclusions— Our findings suggest that cytokines in the IL-1 family may represent therapeutic targets in CAD. The ability of statins to modulate these cytokines in an anti-inflammatory direction underscores their immunomodulatory potential.
Key Words: interleukins • coronary disease • inflammation • statins
This article has been cited by other articles:
 |
|
 |
|
  B. Halvorsen, E. Heggen, T. Ueland, C. Smith, W. J Sandberg, J. K Damas, K. Otterdal, S. Tonstad, and P. Aukrust Treatment with the PPAR{gamma} agonist rosiglitazone downregulates interleukin-1 receptor antagonist in individuals with metabolic syndrome Eur. J. Endocrinol., February 1, 2010; 162(2): 267 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Klingenberg and G. K. Hansson Treating inflammation in atherosclerotic cardiovascular disease: emerging therapies Eur. Heart J., December 1, 2009; 30(23): 2838 - 2844. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. D. Lamon and D. P. Hajjar Inflammation at the Molecular Interface of Atherogenesis: An Anthropological Journey Am. J. Pathol., November 1, 2008; 173(5): 1253 - 1264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. I. Boesen, J. M. Sasser, M. A. Saleh, W. A. Potter, M. Woods, T. D. Warner, J. S. Pollock, and D. M. Pollock Interleukin-1{beta}, but not interleukin-6, enhances renal and systemic endothelin production in vivo Am J Physiol Renal Physiol, August 1, 2008; 295(2): F446 - F453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Smith, B. Halvorsen, K. Otterdal, T. Waehre, A. Yndestad, B. Fevang, W. J. Sandberg, U. M. Breland, S. S. Froland, E. Oie, et al. High levels and inflammatory effects of soluble CXC ligand 16 (CXCL16) in coronary artery disease: down-regulatory effects of statins Cardiovasc Res, July 1, 2008; 79(1): 195 - 203. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. M. Breland, B. Halvorsen, J. Hol, E. Oie, G. Paulsson-Berne, A. Yndestad, C. Smith, K. Otterdal, U. Hedin, T. Waehre, et al. A Potential Role of the CXC Chemokine GRO{alpha} in Atherosclerosis and Plaque Destabilization: Downregulatory Effects of Statins Arterioscler Thromb Vasc Biol, May 1, 2008; 28(5): 1005 - 1011. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. T. Tuomisto, H. Lumivuori, E. Kansanen, S.-K. Hakkinen, M. P. Turunen, J. V. van Thienen, A. J. Horrevoets, A.-L. Levonen, and S. Yla-Herttuala Simvastatin has an anti-inflammatory effect on macrophages via upregulation of an atheroprotective transcription factor, Kruppel-like factor 2 Cardiovasc Res, April 1, 2008; 78(1): 175 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. T. Miller, P. M. Ridker, P. Libby, and D. J. Kwiatkowski Atherosclerosis: The Path From Genomics to Therapeutics J. Am. Coll. Cardiol., April 17, 2007; 49(15): 1589 - 1599. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Devaraj, E. Chan, and I. Jialal Direct Demonstration of an Antiinflammatory Effect of Simvastatin in Subjects with the Metabolic Syndrome J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4489 - 4496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Smith, J. K. Damas, K. Otterdal, E. Oie, W. J. Sandberg, A. Yndestad, T. Waehre, H. Scholz, K. Endresen, P. S. Olofsson, et al. Increased Levels of Neutrophil-Activating Peptide-2 in Acute Coronary Syndromes: Possible Role of Platelet-Mediated Vascular Inflammation J. Am. Coll. Cardiol., October 17, 2006; 48(8): 1591 - 1599. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Blankenberg, T. Godefroy, O. Poirier, H. J. Rupprecht, S. Barbaux, C. Bickel, V. Nicaud, R. Schnabel, F. Kee, C. Morrison, et al. Haplotypes of the Caspase-1 Gene, Plasma Caspase-1 Levels, and Cardiovascular Risk Circ. Res., July 7, 2006; 99(1): 102 - 108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S Kornman Interleukin 1 genetics, inflammatory mechanisms, and nutrigenetic opportunities to modulate diseases of aging Am. J. Clinical Nutrition, February 1, 2006; 83(2): 475S - 483S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Koh, S. H. Han, and M. J. Quon Inflammatory Markers and the Metabolic Syndrome: Insights From Therapeutic Interventions J. Am. Coll. Cardiol., December 6, 2005; 46(11): 1978 - 1985. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Cheng, Y.-H. Liao, J. Zhang, B. Li, H. Ge, J. Yuan, M. Wang, B. Lu, Y. Liu, and Y. Cheng Effects of Atorvastatin on Th polarization in patients with acute myocardial infarction Eur J Heart Fail, December 1, 2005; 7(7): 1099 - 1104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Damas, A. Boullier, T. Waehre, C. Smith, W. J. Sandberg, S. Green, P. Aukrust, and O. Quehenberger Expression of Fractalkine (CX3CL1) and its Receptor, CX3CR1, Is Elevated in Coronary Artery Disease and Is Reduced During Statin Therapy Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2567 - 2572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. C. Fonarow In-Hospital Initiation of Statin Therapy in Acute Coronary Syndromes: Maximizing the Early and Long-term Benefits Chest, November 1, 2005; 128(5): 3641 - 3651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Nissen High-Dose Statins in Acute Coronary Syndromes: Not Just Lipid Levels JAMA, September 15, 2004; 292(11): 1365 - 1367. [Full Text] [PDF]
|
|